Lamb, based on the novel by Bonnie Nadzam, traces the self-discovery of David Lamb in the weeks following the disintegration of his marriage and the death of his father. Hoping to regain some faith in his own goodness, he turns his attention to Tommie, an awkward and unpopular eleven-year-old girl. Lamb is convinced that he can help her avoid a destiny of apathy and emptiness, and takes Tommie for a road trip from Chicago to the Rockies, planning to initiate her into the beauty of the mountain wilderness. The journey shakes them in ways neither expects.

Johnathan is a nine-year-old boy who loves sea monsters, and his 300 lb. pet pig, named Wee Wee. Unlike most kids, Johnathan has nystagmus, which makes his eyes "flutter." He also suffers from severe narrow angle glaucoma; an acute condition that if untreated can lead to permanent blindness. JoLynn cares for Johnathan alone while her singer/songwriter husband David travels in search of his big break. To treat Johnathan, she grows hydroponic marijuana to relieve the painful intraocular pressure Glaucoma causes. She cooks the marijuana into brownies and feeds them to him in secret. David's parents, Mark and Linda, live nearby and provide for JoLynn and Johnathan as best they can on a fixed income. Linda is highly critical of JoLynn's ability to raise Johnathan. During her son's absence, Johnathan has become more undisciplined than Linda would like. While Mark tries to keep the peace, he is torn between his wife and their daughter-in-law, who he loves deeply. When JoLynn discovers that Linda is secretly mounting a case for legal custody of Johnathan, JoLynn is forced to forgo the support of her in-laws. The result is a spiral of desperate acts that force JoLynn to make a decision that will change Johnathan's world forever.

Upon release from prison, a solitary man known only as "the Rambler" (Dermot Mulroney) embarks on a mysterious journey en route to reconnecting with his long-lost brother. Traversing treacherous back roads, lost highways, and isolated small towns, he unearths a multitude of bizarre and wickedly depraved slices of Americana.

Five directors tackle five short stories that are all tied together in one sweet, dark, twisted, humorous film about what goes on behind the door of room 316. Each director was given a brief synopsis, eight rules to follow, and one day on set to create their film.